Substances, vaccines and methods for diagnosing and reducing incidences of transplant rejection

Abstract

Methods and products for diagnosing, treating and/or delaying onset of chronic allograft rejection, including cardiac allograft vasculopathy. In an exemplary embodiment of a noninvasive method of screening a cardiac allograft recipient for being at-risk for developing cardiac allograft vasculopathy of the present disclosure, the method comprises the steps of withdrawing at least one biological sample from a cardiac allograft recipient; and analyzing the at least one biological sample for one or more biomarkers indicative of the presence of fibrin deposits within the cardiac allograft microvasculature; wherein detection of the one or more biomarkers indicates that the cardiac allograft recipient is at-risk for or developing cardiac allograft vasculopathy.

1 . A method of diagnosing an allograft recipient for chronic allograft rejection or being at-risk for developing the same, and administering a treatment to the allograft recipient based upon the diagnosis, the method comprising the steps of:
 measuring an amount of a first natural antibody within at least one biological sample containing serum from an allograft recipient; and   comparing the amount of the first natural antibody in the biological sample with the amount of the first natural antibody in a healthy control sample;   wherein a decrease in the amount of the first natural antibody in the sample from the allograft recipient as compared to the amount of the first natural antibody in the healthy control sample indicates a diagnosis of the allograft recipient being either at-risk for or experiencing chronic allograft rejection; and   administering a treatment to the allograft recipient based on the diagnosis.   
     
     
         2 . The method of  claim 1 , further comprising the step of withdrawing at least one biological sample from the allograft recipient. 
     
     
         3 . The method of  claim 1 , wherein the allograft comprises a cardiac allograft and the chronic allograft rejection comprises cardiac allograft vasculopathy. 
     
     
         4 . The method of  claim 1 , wherein the first natural antibody is selected from the group consisting of immunoglobulin M, immunoglobulin G, and immunoglobulin A and the at least one biological sample comprises tissue. 
     
     
         5 . The method of  claim 1 , wherein the at least one biological sample comprises serum or tissue. 
     
     
         6 . The method of  claim 4 , wherein the step of comparing the amount of the first natural antibody in the biological sample with the amount of the first natural antibody in a control sample comprises reacting the at least one biological sample with Arginase 1 and analyzing the degree of reactivity within the sample; and
 wherein the degree of reactivity in the at least one biological sample is indicative of immunoglobulin M anti-phosphorylcholine, immunoglobulin G anti-phosphorylcholine, or immunoglobulin A anti-phosphorylcholine levels in the allograft recipient's serum.   
     
     
         7 . The method of  claim 1 , wherein at least one of the biological samples comprises serum and the first natural antibody comprises immunoglobulin M anti-phosphorylcholine, immunoglobulin G anti-phosphorylcholine, or immunoglobulin A anti-phosphorylcholine. 
     
     
         8 . The method of  claim 4 , further comprising the step of associating the patient with an increased risk of developing chronic allograft rejection when the amount of the first natural antibody is less than about 20 units/ml of serum. 
     
     
         9 . The method of  claim 1 , wherein if the diagnosis of the allograft recipient is indicated as being at-risk for or experiencing chronic allograft rejection, the method further comprises the step of selectively enhancing a natural antibody-mediated innate immune response in the allograft recipient. 
     
     
         10 . The method of  claim 9 , wherein the step of selectively enhancing a natural antibody-mediated immune response further comprises increasing levels of immunoglobulin M and/or immunoglobulin G anti-phosphorylcholine natural antibodies in the allograft recipient's serum. 
     
     
         11 . The method of  claim 10 , wherein:
 the step of increasing levels of immunoglobulin M and/or immunoglobulin G anti-phosphorylcholine natural antibodies in the allograft recipient's serum further comprises administering a vaccine to the allograft recipient, the vaccine comprising a composition for preventing or treating chronic allograft rejection; and   the composition comprises a therapeutically effective amount of phosphorylcholine sufficient to initiate the production of anti-phosphorylcholine natural antibodies in a mammal following administration thereto.   
     
     
         12 . The method of  claim 11 , wherein the vaccine is administered before chronic allograft rejection is detected. 
     
     
         13 . The method of  claim 10 , wherein the increased levels of immunoglobulin M and/or immunoglobulin G anti-phosphorylcholine natural antibodies in the allograft recipient's serum induces alternative M2 anti-inflammatory macrophage polarization. 
     
     
         14 . The method of  claim 10 , further comprising the step of clearing the allograft of damaged cells by way of inducing alternative M2 anti-inflammatory macrophage polarization. 
     
     
         15 . The method of  claim 10 , wherein the step of selectively enhancing a natural antibody-mediated immune response results in the reduction or prevention of atherosclerosis in the allograft. 
     
     
         16 . A noninvasive method of screening a cardiac allograft recipient for being at-risk for developing cardiac allograft vasculopathy, the method comprising the steps of:
 withdrawing at least one biological sample from a cardiac allograft recipient; and   analyzing the at least one biological sample for one or more biomarkers indicative of the presence of fibrin deposits within the cardiac allograft microvasculature;   wherein detection of the one or more biomarkers indicates that the cardiac allograft recipient is at-risk for or developing cardiac allograft vasculopathy; and   administering a treatment comprising inducing alternative M2 anti-inflammatory macrophage polarization if allograft recipient is at-risk for or developing cardiac allograft vasculopathy.   
     
     
         17 . The method of  claim 16 , wherein:
 the step of withdrawing the at least one biological sample comprises withdrawing serum from the cardiac allograft recipient; and   at least one of the biomarkers is selected from the group comprising:
 an elevated level of cardiac troponin I in the serum as compared to a healthy control serum sample, and 
 detection of reduced anticoagulant and fibrinolytic capacities of the serum as compared to the healthy control serum sample. 
   
     
     
         18 . The method of  claim 16 , wherein:
 the step of withdrawing the at least one biological sample comprises extracting a biopsy sample of the cardiac allograft, the biopsy sample comprising endothelial cells; and   at least one of the biomarkers is selected from the group comprising:
 detection of up-regulation of endothelial intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells from the biopsy sample as compared to a control tissue sample, and 
 detection of an elevated nuclear factor-kappa B (NF-κB) nuclear expression in the endothelial cells from the biopsy sample as compared to a control tissue sample. 
   
     
     
         19 . The method of  claim 16 , wherein the treatment comprises a composition for preventing or treating chronic allograft rejection, the composition comprising a therapeutically effective amount of phosphorylcholine sufficient to initiate the production of anti-phosphorylcholine natural antibodies in a mammal following administration thereto. 
     
     
         20 . A noninvasive method of diagnosing the early onset of chronic allograft rejection, the method comprising the steps of:
 measuring an amount of a first natural antibody within at least one biological sample from a cardiac allograft recipient;   comparing the amount of the first natural antibody in the biological sample with the amount of the first natural antibody in a healthy control sample;   analyzing the at least one biological sample for one or more biomarkers indicative of the presence of fibrin deposits within the cardiac allograft microvasculature;   wherein a decrease in the amount of the first natural antibody in the sample from the cardiac allograft recipient as compared to the amount of the first natural antibody in the healthy control sample indicates a diagnosis of the allograft recipient being either at-risk for or developing chronic allograft rejection; and   administering a treatment option if detection of the one or more biomarkers in the at least one biological sample indicates that the cardiac allograft recipient is at-risk for or developing cardiac allograft vasculopathy, wherein the treatment option induces alternative M2 anti-inflammatory macrophage polarization in the allograft recipient.